Orofacial clefts (OFCs), particularly nonsyndromic cleft lip with or without cleft palate (NS CL/P) are a major public health problem, affecting one in every 500-1000 births worldwide. Therefore, many research groups have attempted to identify genetic loci contributing to the etiology of CL/P, with some recent successes. It appears that the genetic contribution to the etiology of oral-facial clefting is complex, probably heterogeneous, and probably (at least in some cases) due to interacting effects of multiple loci. This proposal is a revision application for the parent grant (#2-R01-DE016148).The parent grant has a funding period of August 12, 2008 to June 30, 2013. The overarching goals of the parent grant and also of this supplement are (1) to investigate subclinical phenotypic features in general NS CL/P families (i.e. simplex as well as multiplex, plus in other ethnicities) in order to determine the potential clinical relevance of these phenotypes;(2) to investigate further how these features can clarify the observed penetrance patterns of CL/P in families;and (3) to perform genome-wide linkage and genome-wide association studies to identify genes related to the expanded phenotypic features. The parent grant is recruiting Caucasian families (Pittsburgh, Texas, Hungary, Denmark). In this revision application, we propose extending recruitment to South American (Guatemala, Argentina) and Asian (China, Philippines) sites in order to expand the protocol to additional high-risk populations. Successful completion of this project will allow a better understanding of the etiology and phenotypic spectrum of CL/P, and will eventually lead to improved recurrence risk estimates and treatments for CL/P PROJECT RELEVANCE: This project will identify physical features (phenotypes) associated with cleft lip and palate birth defects, and will identify genes related to these phenotypes. This knowledge will lead to improved genetic counseling in families with cleft lip and palate, and also will eventually lead to improved therapies for these very common birth defects.